Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy

Background Recent experimental and clinical data indicate that abnormal central and peripheral immune reactions contribute to the progression of chronic heart failure, and that immunomodulation may be an important therapeutic approach in this syndrome. Aims We sought to study the effects of growth hormone (GH) administration on circulating pro-inflammatory/anti-inflammatory cytokine balance, and to investigate whether these GH-induced immunomodutatory effects are associated with the improvement of left ventricutar (LV) contractile performance in idiopathic dilated cardiomyopathy (DCM) patients. Methods Plasma pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interteukin-6 (IL-6), granulocyte-macrophage colony-stimutating factor (GM-CSF) and its soluble receptor (sGM-CSFR), chemotactic cytokine macrophage chemoattractant protein-1 (MCP-1), soluble adhesion molecules intercellular adhesion motecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1), and, finally, anti-inflammatory cytokines interteukin-10 (IL-10) and transforming growth factor-beta2 (TGF-beta2) were measured (ELISA method) in 12 patients with DCM (NYHA class 111; LV ejection fraction: 23.6 +/- 1.7%) before and after a 3-month subcutaneous administration of GH 4 IU every other day (randomized crossover design). Peak oxygen uptake (VO2 max), LV dimensions, LV mass index, end-systolic watt stress (ESWS), mean velocity of circumferential fibre shortening (Vcfc), and contractile reserve (change of ratio Vcfc/ESWS after dobutamine administration) were also determined at the same period. Results Treatment with GH produced a significant reduction in plasma TNF-alpha (7.8 +/- 1.1 vs 5.5 +/- 0.9pg/ml, P=0.013), IL-6 (5.7 +/- 0.5 vs 4.7 +/- 0.4 pg/mt, P=0.043), GM-CSF (27.3 +/- 1.7 vs 23.3 +/- 1.8 pg/ml, P=0.042), sGM-CSFR (4.0 +/- 0.4 vs 3.2 +/- 0.4 ng/ml, P=0.039), MCP-1 (199 +/- 5 vs 184 6 pg/ml, P=0.048), sICAM-1 (324 +/- 34 vs 274 +/- 27 ng/ml, P=0.008) and sVCAM-1 (1238 +/- 89 vs 1043 +/- 77ng/mt, P=0.002) in DCM patients. A significant increase in ratios IL-10/TNF-alpha (1.9 +/- 0.3 vs 3.5 +/- 0.9, P=0.049), IL-10/IL-6 (2.6 +/- 0.6 vs 3.2 +/- 0.5, P=0.044) and TGF-beta2/TNF-alpha (3.1 +/- 0.6 vs 4.4 +/- 0.6, P=0.05) was also found with GH therapy. A significant reduction in ESWS (841 +/- 62 vs 634 +/- 48 gr/cm(2), P=0.0026) and LV end-systotic volume index (LVESVI, 128 +/- 12 vs 102 +/- 12 ml, P=0.035) as welt as a significant increase in posterior wall thickness (PWTH, 9.2 +/- 0.5 vs 10.3 +/- 0.6 mm, P=0.034), contractile reserve (0.00029 +/- 0.0001 vs. 0.00054 +/- 0.0001 circ*cm(2)/ gr*s, P=0.00028) and VO2max (15.3 +/- 0.7 vs 17.1 +/- 0.9 mi/kg/min, P=0.002) were observed after GH administration. Good correlations were found between GH-induced increase in contractile reserve and the increases in VO2max (r=0.63, P=0.028), IL-10/TNF-alpha (r=0.69, P=0.011) and TGF-beta2/TNF-alpha (r=0.58, P=0.046) ratios, as well as the reduction in plasma TNF-alpha levels (r=-0.86, P=0.0004). Conclusions GH administration modulates beneficially circulating cytokine network and soluble adhesion molecules in patients with DCM, whilst enhancing contractile reserve and diminishing LV volumes. These GH-induced anti-inflammatory effects may be associated with the improvement in LV contractile performance and exercise capacity as wet[ as with the reverse of LV remodelling of patients with DCM. (C) 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.